2010, Vol. 5 No. 2, Article 63
Benzimidazoles in a Wormy World
A. K. Dubey and P. K. Sanyal*
Department of Parasitology
*Corresponding Author; e-mail address: email@example.com
Anthelmintics are the only weapons available to combat parasite menace in livestock. In fact, even if with the availability of any alternative control measures in future, viz., vaccines, biological control, resistant hosts etc., anthelmintics will definitely be playing its role in the so called “Sustainable Parasite Control Programme.” The black side of this story is the emergence of resistance to three major classes of anthelmintics, viz., levamisole, rafoxanide and benzimidazole. This is particularly important at present in small ruminants. Although faced with this obstacle it is important to remember that the majority of the anthelmintics are still efficacious in most livestock, particularly in large ruminants where only one report of anthelmintic resistance is reported so far from North India. One should not be complacent with this fact, but look at it from a different angle that the problem is emerging and looms large over large ruminants. Further, discovery of a new class of anthelmintics is very time and capital intensive and it is expected that a new drug with a different mode of action will only be available in the next decade. Therefore, the present day chemicals will continue to be used for parasite control.
The problem of helminth infection is vast by anyone’s reckoning and is of equal interest to the
veterinary surgeon and clinician. To say that helminths are ubiquitous is almost an understatement; as parasite of livestock and humans they represent the single most important group of infections on the planet. Although many separate species are involved.
THE SYNTHESIS AND CHEMISTRY OF CERTAIN ANTIHELMINTIC BENZIMIDAZOLES
A basis for interest in the benzimidazole ring system as a nucleus from which to develop potential chemotherapeutic agents was established in the 1950’s when it was found that 5,6,-dimethyl-l-(alpha-D-ribofuranosyl) benzimidazole was an integral part of the structure of the vitamin B12. As a result of this interest and extensive studies on health related arena that has benefited greatly has been the treatment of the parasitic diseases. The discovery of thiabendazole in 1951 further spurred chemists around the world to design and synthesize several thousand benzimidazoles for screening for antihelminthic activity but less than 20 of them have reached commercial use. Much of this work has been done by pharmaceuticals companies and is only reported in the patent literature (Townsend and Wise, 1990).
MODE OF ACTION OF BENZIMIDAZOLES
Benzimidazoles represent the only class of truly broad-spectrum anthelmintics and are also showing activity against fungi and mammalian cells. With the discovery of thiabendazole in 1961 general pattern of benzimidazole as a class of low doses broad spectrum antheminthic with a high therapeutic index was established. The subsequent cascade of patents within the next 25 years led to the experimental or
commercial development of further 15 benzimidazoles and benzimidazole prodrugs. Central to the success of benzimidazole is their selected toxicity for helminths. Since the mid 1960’s the mode of action of benzimidazole
has been extensively investigated and our understanding regarding how benzimidazoles act has undergone radical reappraisals. In a review Lacey (1990) concluded that despite of the diverse effects of benzimidazoles at the biochemical and cellular levels the primary mode of action of these drugs involves their interaction with the eukaryotic cytoskeletal protein, tubulin.
THE METABOLISM OF BENZIMIDAZOLE ANTHELMINTHICS
Throughout their lifetime, mammals
are exposed to large number of compounds foreign to normal
intermediary metabolism. As a result an intricate system of
detoxification has evolved that combines enzyme catalyzed metabolic conversion, non-specific chemical reaction and fine-tuned excretion pathway. The process is generally based on the transformation of lipophilic xenobiotic compound to more polar hydrophilic product that can
be easily eliminated.
BENZIMIDAZOLE OF VETERINARY USES
The benzimidazoles were introduced into the animal health market primarily for the control of gastro-intestinal nematodes (Campbell, 1990). They were formulated not only for use in farm animals (sheep, cattle, goat, swine, poultry) but also for companion animals (horse and dog). Their use quickly became widespread because they offer major advantages over previous medication in terms of breadth of spectrum and efficacy against immature stages and safety for the host animals. They did not cause a setback due to drug toxicity and it was possible to demonstrate the economic advantages of routine strategic treatment even under condition of mild parasitism. The benzimidazoles also provided an action of epidemiological rather than therapeutic importance in that the eggs of many nematodes when exposed to one of these drugs in the gut contents of treated animals failed to hatch after deposition on pasture. Some benzimidazoles offered an extended spectrum with activity not only against extra-intestinal nematodes but also against some tapeworms and flukes. Modern benzimidazoles include several compounds, the prodrugs, being administered in form of compounds that are not themselves benzimidazoles but which are metabolised by the treated animal into anthelmintically active benzimidazoles.
Benzimidazole resistance has emerged as the most serious problem confronting the successful control of G.I. nematodes in ruminants, especially in small ruminants, in several parts of the world (Nari, 2005). The first report of anthelmintic resistance in Haemonchus contortus, in India was by Varshney and Singh (1976), against phenothiazene and thiabendazole at State Sheep and Wool Research Station, Pashulok, Rishikesh, U.P. (now in Uttaranchal). However, there was no report of anthelmintic resistance from 1976 to 1990. Since 1990 onwards, there has been a renewed interest in India on this aspect and a considerable number of reports of anthelmintic resistance observed in G.I. nematodes are pouring-in from various parts of the country (Yadav and Gupta, 2005). To circumvent the problem of drug resistance, the only realistic strategy would be to develop novel non-chemical approaches that decrease the need or treatment and to use the anthelmintics that remain effective in a more intelligent manner (Sanyal, 2005).
For brevity, only fairly recent review articles are cited. We express sincere apology to the original authors.
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Hennessy, D.R. 1997. Physiology, Pharmacology and Parasitology. International Journal for Parasitology 27 : 145-152.
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Lacey, E. 1990. Mode of action of benzimidazoles. Parasitology Today 6 (4) : 112-115.
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Varshney, T.R. and Singh, Y.P. 1976. A note on development of resistance of Haemonchus contortus worms against phenothiazine and thiabendazole in sheep. Indian J. Anim. Sci., 46: 666-668.
Yadav, C.L. and Gupta, Rajat. 2005. Status of anthelmintic resistance in gastrointestinal nematodes in India. In : Proceedings of FAO Symposium on Integrated Animal Parasite Management : From Academic Interest To Reality (eds. P.K. Sanyal, A.K. Sarkar, N.K. Patel, S.C. Mandal and S. Pal), College of Veterinary Science & AH, Anjora, Durg, pp. 9-22.
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